Abstract Intrauterine growth restricted (IUGR) newborns have an increased risk of adult obesity and metabolic syndrome. Importantly, newborns with the lowest birth weight have 18 times more risk of metabolic syndrome than newborns with heaviest birth weight. We have established a rat model that recapitulates this paradox. Specifically, maternal food restriction (MFR) during the second-half of rat pregnancy results in IUGR newborns. When provided normal nursing and postweaning diet (FR/AdLib), these offspring demonstrate rapid catch-up growth and adult obesity with lipid abnormalities. Mechanistically, our studies indicate that increased adiposity in FR/AdLib offspring is a result of programmed upregulation (prior to the development of obesity) of the adipogenesis signaling cascade, in particular, the adipogenic transcription factor, PPAR[unreadable]2. Thus, the proposed project will determine the underlying mechanism for this paradoxical upregulation of PPAR[unreadable] in programmed obesity. Notably, our preliminary data implicate the role of PPAR[unreadable] co-regulators. Specifically, (i) decreased co- repressor, NCoR, (ii) increased co-activator, SRC1, and (iii) reduced inhibition of PPAR[unreadable]2 via ERK1/2-mediated phosphorylation. These may all contribute to PPAR[unreadable]-mediated programmed adipogenesis. We thus hypothesize that (1) down regulation of PPAR[unreadable]2 co-repressors is the mechanism for PPAR[unreadable]-mediated adipogenesis in FR/AdLib offspring, and (2) epigenetic modification of these factors explains the altered gene expression, as well as offers the opportunity for preventative or therapeutic interventions. To confirm the putative role of PPAR[unreadable], in vivo studies will stimulate PPAR[unreadable] (rosiglitazone) and inhibit (BADGE) PPAR[unreadable] directly and via increased co-repressor levels (resveratrol), and determine the impact of these modifications on downstream lipid targets. We will confirm the role of co-repressors (SIRT1, SMRT and NCoR) and/or co- activators (SRC1 and TIF2) using lentivirus and siRNA technology in primary adipocyte cell cultures. We will further investigate the effects of PPAR[unreadable]2 on its downstream lipid targets. To determine the mechanism of altered gene expression, we will examine the epigenetic modification of co-repressor/co-activator and PPAR[unreadable], while exploring the heritability of epigenetic modifications. In all studies, we will contrast the mechanisms of enhanced adipogenesis due to programmed versus diet-induced metabolic syndrome (DIMS). This series of experiments utilizes integrative techniques that involve molecular biology, cellular physiology, and whole body physiology. These studies will provide major new insights and potential therapeutic interventions for gestationally programmed adipogenic mechanisms.